Annually, approximately 2 million Americans suffer a moderate to severe traumatic brain injury (TBI). These injuries produce enduring disabilities that include cognitive, sensory, motor and emotional impairments. The associated health care costs from these injuries are staggering. One of the most at risk populations are the elderly, who can show twice the mortality of younger patients. Increasing age has also been shown to result in worse behavioral and pathological outcome. Confounding this major public health issue is the fact that currently there are very few pharmacological treatment options for patients who have suffered TBI. In addition, most preclinical therapeutics are never tested in older animals and many newly synthesized drugs fail in various stages of clinical testing. Given the fact that newly synthesized drugs fail in clinical trials it seems reasonable to begin to examine the potential efficacy of more natural substances. It has recently been demonstrated that administration of vitamin B3 (B3) following cortical contusion injury (CCI) resulted in a significant improvement in recovery of sensorimotor and cognitive function, as well as in a reduction of many of the secondary pathophysiological changes that occur following injury (i.e., neurodegeneration, edema formation and reactive gliosis). The proposed research will further investigate the preclinical efficacy of B3 utilizing an animal model of chronic and severe TBI-related behavioral impairments. We will use middle-aged (15 month old) rats in the CCI model to produce the severe deficits in order to test B3's ability to improve these deficits. The specific aims of this study are to: 1) determine if administration of B3 following injury can significantly reduce the sensorimotor and cognitive impairments seen following TBI in middle- aged rats; 2) determine if administration of B3 following injury in middle-aged rats can reduce injury-induced edema following TBI; 3) determine if administration of B3 following injury can reduce neuronal death, apoptosis and reactive gliosis following injury in middle-aged rats; and 4) determine if increased age has a deleterious effect on cerebral edema, neurodegeneration, apoptosis, and GFAP proliferation following TBI. The research proposed here will determine if B3 can overcome the severe behavioral and pathological outcomes associated with TBI in middle-aged subjects. This will be a critical step in determining the parameters for the development of B3 as a clinical treatment for TBI. [unreadable] [unreadable] [unreadable]